Hepatic encephalopathy (HE) is a common neuropsychiatric complication of advanced liver disease. The pathogenesis of this reversible syndrome is unknown. Therapy for this problem consequently has remained largely empirical. Recently it has been reported that specific benzodiazepine (BZ) receptor antagonists devoid of effect in normal controls reverse the neurobehavioral and electrophysiologic abnormalities in both animals and humans with HE. Subsequent studies have detected substantial quantities of BZ-like activity in brain extracts and physiological fluids in HE. The hypothesis to be tested in this proposal is that HE is mediated by this substance which simulates the action of neurodepressant BZ compounds. The initial investigations to be performed will isolate and identify the substance using chromatography and mass spectrometry techniques. Once the substance is isolated studies will be performed to establish if it is present in normal controls and other disease states. Correlations between the level of this substance and the degree of severity of HE will be established. Concurrently, investigations regarding the source of the substance will be undertaken in humans and animals. Isolation of a novel compound will necessitate detailed in vitro and neurobehavioral studies to identify its neuromodulatory properties. These studies are important not only to the understanding and treatment of HE, but may for the first time identify a compound which mediates a neurological effect via the BZ receptor.